PROJECT SUMMARY Human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome are significant sources of morbidity and mortality worldwide. Currently, there are 35 million people world-wide living with the disease. Infection with HIV increases the risk for human papillomavirus (HPV) infection. In fact, HIV/AIDS patients are infected with a high number of multiple HPV types compared to non-HIV patients and the diversity of HPV types in HIV/AIDS patients seem to be different from patients without HIV/AIDS; additionally, this diversity in HPV types differs from one geographic region to another. HPV (like HIV) is a sexually transmitted agent that can be transmitted via oral sex. HPV infection is associated with a growing percentage of Head and Neck cancers (HNCs); thus HIV/AIDS patients are at a high risk for developing HNCs. As a matter of fact, 60% of HIV patients have HPV-associated oropharyngeal cancers, a form of HNCs. Two prophylactic vaccines have been approved within the last decade and one within the past five months to prevent against HPV infections. It is estimated that the most recently approved Gardasil-9 vaccine will protect against HPV types associated with about 90% of cancers. Unfortunately the vaccine will not protect against HPV types that are not included in the vaccine especially some cancer causing HPV types that HIV patients are infected with. Additionally the potentials of the vaccine to protect against oral HPV infection are not well known and the vaccines are temperature-sensitive making them less suitable in the developing world where more HIV patients with HPV infections reside. In this proposal, we will develop and test the immunogenicity of a multi-epitope L2 bacteriophage virus-like particle (VLP) vaccine that can offer more broader levels of protection against oral HPV infection in HIV patients. We will use a highly immunogenic model bacteriophage VLP platform, to enhance the immunogenicity of three independent cross-neutralizing epitopes derived from the alignment of sequences from the minor capsid protein (L2) of 23 HPV types. We will assess the immunogenicity of the multi-epitope L2 VLP vaccine at the site of HPV entry into the body, the oral cavity. We will explore strategies to enhance oral immune responses by immunizing with a combination of two or more mucosal adjuvants. We will further assess the feasibility of formulating the L2 VLPs together with a combination of adjuvants into a dry product that will be suitable in the developing world where the risks of HPV-associated HNCs (from high prevalence of HIV infection) are increasing. Our experience with the development and testing of L2 VLPs vaccine in an animal model for HPV infection demonstrates our potential to pursue this project to completion.